The Unique Properties of Dipeptidyl-peptidase IV (DPP IV I CD26) and the Therapeutic Potential of DPP IV Inhibitors

Abstract

This review deals with the properties and functions of dipeptidyl peptidase IV (DPP IV, EC 3.4.14.5). This membrane anchored ecto-protease has been identified as the leukocyte antigen CD26. The following aspects of DPP IV/CD26 will be discussed: the structure of DPP IV and the new family of serine proteases to which it belongs, the substrate specificity, the distribu­tion in the human body, specific DPP IV inhibitors and the role of CD26 in the intestinal and renal handling of proline containing peptides, in cell adhesion, in peptide metabolism, in the immune system and in HIV infection. Especially the latest developments in the search for new inhibitors will be reported as well as the discovery of new natural substrates for DPP IV such as the glucagon-like peptides and the chemokines. Finally the therapeutical perspectives for DPP IV inhibitors will be discussed.

Design, Synthesis, and SAR of Potent and Selective Dipeptide-Derived Inhibitors for Dipeptidyl Peptidases

“…A 1000-fold decrease in potency of d -Dab-Pip ( 9.8 ) confirms the importance of the l -configuration of the P 2 -amino acid for DPP II inhibition. A similar result is published for DPP IV inhibitors . Like for DPP IV, the low potency of Z-Dab-Pip ( 9.10 ) shows the importance of a free α-aminofunction and proves that DPP II is an exopeptidase.…”

“…Indeed, the crystal structure of DPP IV shows a hydrophobic pocket that is optimally suited to fit five-membered rings. 29 Recognizing the importance of the piperidine ring, a broad series of aminoacyl piperidides (Pip) (9) with basic and neutral amino acids at P 2 were synthesized. Results are summarized in Table 4.…”

“…The resembling substrate specificity and catalytic mechanism make this a challenging task. In contrast to DPP IV, 9,10 only a few DPP II inhibitors are reported. They will be summarized here.…”

“…DPP IV has been studied extensively over the last three decades and a broad array of diverse functional properties in the immune, nerve, and endocrine system is suggested. − DPP IV is bound to the cell membrane and expressed quite ubiquitously in mammalian tissues. In the hematopoietic system it was identified as the leukocyte antigen CD26.…”

The Multiple Biological Functions of Dipeptidyl Peptidase-4 in Bone Metabolism

“…Furthermore, DPP4 also has a costimulatory function by binding to CXCR4 ( 32 ), M6P/IGF-IIR ( 33 ), TCR/CD3 ( 30 ), CD45 (protein tyrosine phosphatase) ( 34 ), caveolin-1 ( 36 ), CARMA1 ( 37 ), and fibronectin III ( 38 , 39 ). Synthetic inhibition or deficiency of DPP4 results in impaired development and maturation of naïve T cells ( 122 – 124 ). In addition, DPP4/CD26 plays an essential role in T cell differentiation.…”